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J Med Genet 49:731-736 doi:10.1136/jmedgenet-2012-101251
  • Developmental defects

The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy

  1. Christel Thauvin-Robinet1,2
  1. 1Equipe émergente GAD EA 4271 (Génétique des Anomalies du développement), IFR Santé STIC, Université de Bourgogne, Dijon, France
  2. 2Centre de Génétique et Centre de Référence Anomalies de Développement et Syndromes Malformatifs de l'interrégion Grand-Est, Hôpital d'Enfants, CHU, Dijon, France
  3. 3Département de Génétique Médicale, Laboratoire de génétique moléculaire, CHU de Marseille, Hôpital de la Timone, Marseille, France
  4. 4Laboratoire de Cytogénétique, Plateau Technique de Biologie, CHU de Dijon, Dijon, France
  5. 5Service de médecine infantile III et de génétique clinique, Laboratoire de génétique, Unité de génétique du service néonatale, Maternité régionale de Nancy, Nancy, France
  6. 6Service de Neurologie et Laboratoire d'exploration du système nerveux, Hôpital général, CHU, Dijon, France
  7. 7Laboratoire de Génétique Moléculaire, Plateau Technique de Biologie, CHU, Dijon, France
  8. 8Laboratoire de Génétique et EA 4368, CHU de Nancy, Nancy, France
  9. 9Département de Génétique Médicale, Unité de Génétique Clinique, CHU de Marseille, Hôpital de la Timone, Marseille, France
  1. Correspondence to Dr Christel Thauvin-Robinet, Centre de Génétique et Centre de Référence Anomalies de Développement et Syndromes Malformatifs de l'interrégion Grand-Est, Hôpital d'Enfants, CHU, 10 bd Maréchal de Lattre de Tassigny, Dijon cedex 21079, France;christel.thauvin{at}chu-dijon.fr
  • Received 21 August 2012
  • Revised 27 September 2012
  • Accepted 1 October 2012
  • Published Online First 25 October 2012

Abstract

Background DYRK1A plays different functions during development, with an important role in controlling brain growth through neuronal proliferation and neurogenesis. It is expressed in a gene dosage dependent manner since dyrk1a haploinsufficiency induces a reduced brain size in mice, and DYRK1A overexpression is the candidate gene for intellectual disability (ID) and microcephaly in Down syndrome. We have identified a 69 kb deletion including the 5′ region of the DYRK1A gene in a patient with growth retardation, primary microcephaly, facial dysmorphism, seizures, ataxic gait, absent speech and ID. Because four patients previously reported with intragenic DYRK1A rearrangements or 21q22 microdeletions including only DYRK1A presented with overlapping phenotypes, we hypothesised that DYRK1A mutations could be responsible for syndromic ID with severe microcephaly and epilepsy.

Methods The DYRK1A gene was studied by direct sequencing and quantitative PCR in a cohort of 105 patients with ID and at least two symptoms from the Angelman syndrome spectrum (microcephaly < −2.5 SD, ataxic gait, seizures and speech delay).

Results We identified a de novo frameshift mutation (c.290_291delCT; p.Ser97Cysfs*98) in a patient with growth retardation, primary severe microcephaly, delayed language, ID, and seizures.

Conclusion The identification of a truncating mutation in a patient with ID, severe microcephaly, epilepsy, and growth retardation, combined with its dual function in regulating the neural proliferation/neuronal differentiation, adds DYRK1A to the list of genes responsible for such a phenotype. ID, microcephaly, epilepsy, and language delay are the more specific features associated with DYRK1A abnormalities. DYRK1A studies should be discussed in patients presenting such a phenotype.